Pulmonary hypertension (PHTN) is a serious disorder characterized by an increase in pulmonary vascular resistance and classified clinically as either primary pulmonary hypertension or secondary pulmonary hypertension. In its most common form, pulmonary hypertension usually presents as a manifestation of an obvious or explicable increase in vascular resistance, such as obstruction to blood flow by pulmonary emboli, malfunction of the heart's valves or muscle in handling blood after its passage through the lungs, diminution in pulmonary vessel diameter as a reflex response to hypoventilation and/or low oxygenation, or a mismatch of vascular capacity and essential blood flow, such as shunting of blood in congenital abnormalities or surgical removal of lung tissue. Such pulmonary hypertension is referred to as secondary pulmonary hypertension. Secondary pulmonary hypertension may be a result of chronic obstructive or interstitial lung disease, recurrent pulmonary emboli, liver disease, or pre-existing heart disease.
Pulmonary hypertension where increased vascular resistance is without an obvious cause is classified as primary pulmonary hypertensions (PPH), and is diagnosed after the exclusion of the causes of secondary pulmonary hypertension. PPH is characterized by an undefined injury to the pulmonary vascular endothelium, resulting in an impaired ability to maintain a relaxed state of vasomotor tone, intense medial hypertrophy, intimal proliferation that compromises the vascular lumen, and a conversion within the pulmonary arterial bed to a procoagulant state that disposes the subject to the development of in situ thrombosis. See S. Rich, “Primary Pulmonary Hypertension,” in Harrison's Principles of Internal Medicine 14th Edition (A. S. Fauci et al., eds., McGraw-Hill, New York (1998)), at p. 1466. Additionally, PPH is inexplicably associated with cirrhosis and portal hypertension. Id. Although the etiology of PPH remains unknown, risk factors linked to its development include essential hypertension, human immunodeficiency virus (HIV), anorexigens, collagen vascular disease, and congenital shunts resulting in increased pulmonary blood flow. Additionally, a genetic basis for the disorder appears to exist. Id.
Despite the diversity of possible causes of the disorder, the disease course of pulmonary hypertension is sadly predictable. Untreated pulmonary hypertension leads to progressive cor pulmonale (enlargement and strain of the right ventricle of the heart, sometimes to the point of failure). Subsequently, a pulmonary crisis characterized by decompensated right heart failure develops. The prognosis for patients with primary pulmonary hypertension is poor, with a median survival time of two to three years from diagnosis. Generally, progress of the disorder is inexorable via syncope and right heart failure, and death is often sudden.
U.S. Pat. No. 5,650,395 to Hurel describes the treatment of pulmonary hyertension by the administration of bombesin antagonists to lower pulmonary blood pressure. U.S. Pat. No. 5,153,222 to Tadepalli et al. describes the treatment of pulmonary hypertension by the administration of benzidine prostaglandins, while U.S. Pat. No. 5,028,628 to Tadepalli et al. describes the treatment of pulmonary hypertension by the administration of non-benzidine prostaglandins. U.S. Pat. No. 5,554,610 to Williams et al. describes the treatment of pulmonary hypertension and related conditions by the inhalation administration of vasodilators such as ganglion blockers, sympathetic nerve blockers and direct vasodilators.
Other known treatments for pulmonary hypertension include the administration of compounds such as calcium channel blockers (e.g., nifedipine or diltiazem), prostacycline, anticoagulants (e.g., warfarin), nitroprusside, hydralazine, nitrous oxide, L-arginine, and digoxin. Unfortunately, several of these methods are associated with serious side effects, including acute right ventricular ischemia, and complications from the catheterization required to administer some of the compounds. In severe cases of pulmonary hypertension, where the condition is refractory to the administration of drugs, lung or heart-lung transplantation is the only effective treatment available to clinicians. However, this treatment has numerous disadvantages due to its inherently invasive nature and the risk of organ rejection. Given the foregoing, a need exists for alternative and effective methods of treating pulmonary hypertension.
As set forth in U.S. Pat. No. 5,641,867 to Stern et al., endothelialmonocyte activating polypeptide II (EMAP II) is a polypeptide of approximately 20 kDa molecular weight. The polypeptide has been has been isolated and cloned, and is not a member of previously described cytokine/chemokine families. EMAP II has been shown to activate endothelial cells and mononuclear cells, potentiating their participation in procoagulant reactions through the induction of tissue factor, and to promote the migration of monocytes and polymorphonuclear leukocytes (PMNs). See A. Asher, et al., J. Immunol. 138, 963-974 (1987) and P. Nawroth, et al., J. Exp. Med. 168, 6637-647 (1988). However, the role of EMAP II in the formation of pulmonary hypertension has heretofore not been described.